Genetic culprit in metabolic disease points to possible treatment

N-linked glycosylation is an important post-translational modification of many proteins in eukaryotes. A critical step in this process involves a carbohydrate attaching to the lipid carrier dolichol. The carrier can then stick a glycan group to a protein prior to it folding into shape. Disruption of protein glycosylation causes congenital disorders of glycosylation (CDGs). Although rare, this can lead to serious symptoms, including developmental delay, heart defects, and brain malformations.

An international team of scientists, led by researchers at the United Arab Emirates University and University of California, United States, performed a genome-wide linkage analysis on a large consanguineous Emirati family living in southern Iran with members diagnosed with a form of CDG. They identified mutations in the gene SRD5A3, which encodes the steroid 5a-reductase type 3.

Human, mouse, and yeast cells carrying this mutated gene showed a near depletion of dolichol in vitro. The researchers identify SRD5A3 as the enzyme that controls the reduction of polyprenol in eukaryote cells to form dolichol, which is then involved in n-linked glycosylation. Thus SRD5A3 plays a pivotal role early in the process of glycosylation.

Dolichol is essential for many critical processes in the body. The researchers found residual amounts of dolichol in cells deficient in SRD5A3. This suggests that another, unknown cellular pathway also produces dolichol, although in smaller amounts, and could explain how eukaryotes survive without SRD5A3.

This newly identified mutation disrupts the earliest stages of the N-linked glycosylation. Based on the study, the researchers suggest that intake of dolichol, which is present in several plants such as spinach and gingko, could help patients with CDG.

Sign-up to receive our e-alert update every two weeks to keep up with everything new on the portal.